Open Access
BMJ An international survey of management
Paediatrics
Open
To cite: Zeilmaker-Roest GA,
Wildschut ED, van Dijk M,
et al. An international survey
of management of pain and
sedation after paediatric cardiac
surgery. BMJ Paediatrics Open
2017;1:e000046. doi:10.1136/
bmjpo-2017-000046
►► Additional material is
published online only. To view
please visit the journal online
(http://​dx.​doi.​org/​10.​1136/​
bmjpo-​2017-​000046).
Received 24 April 2017
Revised 26 May 2017
Accepted 28 May 2017
1
Intensive Care, Erasmus MC
Sophia Children’s Hospital,
Rotterdam, The Netherlands
2
Cardio-Thoracic Surgery,
Erasmus MC, Rotterdam, South
Holland, The Netherlands
3
Intensive Care, Starship
Children’s Hospital, Auckland,
New Zealand
4
Intensive Care, Our Lady’s
Children’s Hospital, Crumlin,
Ireland
Correspondence to
Drs Gerdien A Zeilmaker-Roest; ​
g.​zeilmaker@​erasmusmc.​nl
of pain and sedation after paediatric
cardiac surgery
Gerdien A Zeilmaker-Roest,1,2 Enno D Wildschut,1 Monique van Dijk,1
Brian J Anderson,3 Cormac Breatnach,4 Ad J J C Bogers,2 Dick Tibboel,1 The
Paediatric Analgesia after Cardiac Surgery consortium
Abstract
Objective  The mainstay of pain treatment after paediatric
cardiac surgery is the use of opioids. Current guidelines
for its optimal use are based on small, non-randomised
clinical trials, and data on the pharmacokinetics (PK) and
pharmacodynamics (PD) of opioids are lacking. This study
aims at providing an overview of international hospital
practices on the treatment of pain and sedation after
paediatric cardiac surgery.
Design  A multicentre survey study assessed the
management of pain and sedation in children aged 0–18
years after cardiac surgery.
Setting  Pediatric intensive care units (PICU)of 19
tertiary children’s hospitals worldwide were invited to
participate. The focus of the survey was on type and dose
of analgesic and sedative drugs and the tools used for their
pharmacodynamic assessment.
Results  Fifteen hospitals (response rate 79%) filled
out the survey. Morphine was the primary analgesic in
most hospitals, and its doses for continuous infusion
ranged from 10 to 60 mcg kg-1 h-1 in children aged
0–36 months. Benzodiazepines were the first choice for
sedation, with midazolam used in all study hospitals. Eight
hospitals (53%) reported routine use of sedatives with
pain treatment. Overall, type and dosing of analgesic and
sedative drugs differed substantially between hospitals. All
participating hospitals used validated pain and sedation
assessment tools.
Conclusion  There was a large variation in the type
and dosing of drugs employed in the treatment of pain
and sedation after paediatric cardiac surgery. As a
consequence, there is a need to rationalise pain and
sedation management for this vulnerable patient group.
Introduction
Congenital heart disease accounts for almost
one-third of all congenital defects.1 Adequate
postoperative sedation and pain manage-
ment is important in these patients because
untreated pain can lead to a delayed recovery,
prolonged adverse behavioural consequences
and negative physiological responses.2–4
Morphine is widely used for analgesia
after major surgery in neonates and
children. Several studies on morphine
Zeilmaker-Roest GA, et al. BMJ Paediatrics Open 2017;1:e000046. doi:10.1136/bmjpo-2017-000046
Original article
bmjpo: first published as 10.1136/bmjpo-2017-000046 on 5 July 2017. Downloaded from http://bmjpaedsopen.bmj.com/ on 28 April 2018 by guest. Protected by copyright.
What is already known on this topic?
►► There is large variability in choice and dosing of
analgesics and sedatives after cardiac surgery in
children worldwide.
►► Validated pain and sedation tools were used
extensively.
What this study hopes to add?
►► Insight into clinical protocols on use of analgesics
and sedatives in children after cardiac surgery,
showing large variability in choice and dosing of
analgesics and sedatives.
►► Morphine is the first choice analgesic,
while midazolam is the first choice sedative. Dosing
of both drugs differ considerably between hospitals.
►► Use of validated pharmacodynamics  (PD)
assessment tools is not standard in clinical practise.
Lack of a validated PD assessment tool could result
in oversedation.
pharmacokinetics (PK)/pharmacodynamics
(PD) have resulted in age-specific dosing algo-
rithms in children after non-cardiac surgery.
Ceelie et al showed equipotency of parac-
etamol as primary analgesic as compared with
morphine in neonates and children <1 year
of age after major non-cardiac surgery. It is
currently unclear if these data can be extrap-
olated to children after cardiac surgery.5 6
Postoperative analgosedation in children
after cardiac surgery is mainly achieved with
opioids combined with sedatives. The most
common opioid used is morphine, with doses
ranging from 5 to 80 mcg/kg/h.7 Morphine
is recommended as drug of first choice by
the Association of Paediatric Anaesthetists
of Great Britain and Ireland.8 However,
this guideline is based on small, non-ran-
domised clinical trials. PK data are available
1
Open Access
for the routinely prescribed analgesics and sedatives, but
combined PK/PD data are scarce.
Lynn et al described adequate pain relief after cardiac
surgery with continuous morphine infusions of 10–38.5
mcg/kg/h.  9 10 Even though adequate analgesia can be
achieved, plasma morphine concentrations above 20 ng/
mL have been associated with adverse effects, such as
hypotension and respiratory depression.9 11 Patients with
cyanotic heart defects showed lower morphine require-
ments and higher plasma concentrations compared with
patients with non-cyanotic heart defects, indicating that
type of defect or type of surgery may be associated with
altered PK/PD necessitating different dosing regimens.12
A recent review by Lucas et al13 on pharmacotherapies
in paediatric cardiac critical care provides an extensive
overview of PK of analgesic and sedative drugs used in
children after cardiac surgery but focused less on their
use in protocols for clinical practice. Changes in clear-
ance and volume of distribution (PK) and/or PD due
to the use of cardiopulmonary bypass (CPB), disease
processes, low cardiac output syndrome, surgical proce-
dure and age may alter optimal way of dosing analgesics
and sedatives in children after cardiac surgery.14 These
expected PK/PD differences are not incorporated in
existing guidelines, and it is unclear if they are intro-
duced into local protocols.
While current dosing is commonly titrated to effect
(sedation or pain score), quantification of that effect can
be difficult as pain, and sedation scores are not always
validated for different patient groups. A one-size-fits-all
dosing regimen may lead to oversedation or underse-
dation resulting in less efficacy or increased toxicity. As
clear individualised evidence-based dosing guidelines are
lacking, a wide variety can be expected in clinical prac-
tice.
Our primary objective was to ascertain international
analgosedation practices after paediatric cardiac surgery
with a self-reported survey. Our main focus was the use
of local protocols, choice and dosing range of analgesics
and sedatives, use of pain and sedation scores and the use
of treatment algorithms.
Methods
Design
A self-designed web-based survey (Monkey Survey,
https://​nl.​surveymonkey.​com/) was circulated to
medical specialists in tertiary cardiac care hospitals
who are responsible for the treatment of children after
cardiac surgery. Hospitals were selected based on exper-
tise and yearly conduct of more than 150 paediatric
on-pump cardiac surgical procedures. The survey was
designed by a small focus group consisting of a congen-
ital cardiothoracic surgeon, three paediatric intensivists
and a paediatric cardiac anaesthesiologist because of the
absence of validated questionnaires. The potential respon-
dents were instructed that this survey aimed at collecting
data on the current treatment strategies concerning the
2 Zeilmaker-Roest GA, et al. BMJ Paediatrics Open 2017;1:e000046. doi:10.1136/bmjpo-2017-000046
use of analgesics and sedatives, as well as the tools used
for the measurement of pain and sedation, according to
bmjpo: first published as 10.1136/bmjpo-2017-000046 on 5 July 2017. Downloaded from http://bmjpaedsopen.bmj.com/ on 28 April 2018 by guest. Protected by copyright.
their local protocols and not their personal preference.
The survey has been provided in the appendix.
The survey focused primarily on the choice and dosing
regimens of analgesic and sedative drugs prescribed in
the surveyed institutions as well as the PD assessment
tools that were used in these circumstances. Additional
questions related to the characteristics of the unit.
Potential participants initially received a letter asking
for their involvement in the survey. If they agreed, details
of the survey as well as the link to enter their answers
were provided by email. If necessary, an additional email
to remind the participants about the survey was sent 2
and 4 weeks after the initial letter. Data were collected
between June and August 2014.
Ethical approval was not needed for this study, since
no patients are involved neither person-related questions
are raised to the individual hospitals.
Results
Hospital characteristics
A total of 19 hospitals on three different continents were
willing to participate; 15 (response rate 79%) hospitals
completed the survey in full. Twelve respondents (80%)
were from European hospitals. Three respondents were
from non-European hospitals based in New Zealand,
Australia and Canada. Non-respondents were based in
the USA (n=1), UK (n=2) and China (n=1). Respondents
were physicians, mainly paediatric intensivists or paedi-
atric cardio-anaesthesiologists who work in paediatric
cardiac critical care units. Two paediatric intensivists
reported that they had consulted a paediatric cardio-an-
aesthesiologist on questions relating to the perioperative
management.
The participating hospitals perform a total of over 3000
on-pump paediatric cardiosurgical procedures annually
with a postoperative ICU stay ranging between 2 and 7
days.
The number of procedures per age category varied
between hospitals; however, about two-third of the proce-
dures were performed in children under the age of 1 year.
Medication
Table 1 shows the type and dosing of reported analgesics.
Table 2 shows the type and dosing of reported sedatives.
Both tables show the results for treatment protocol in
neonates and children until the age of 2 years. There was
a wide range of choices and dosing regimens of drugs
reported for both analgesics and sedatives. Moreover,
polypharmacy is often used to accomplish the desired
effects for both analgesia and sedation. Eleven different
analgesics and eight different sedatives were reported.
None of the hospitals based analgosedation according
to protocol on cardiac diagnosis, severity scores or type
of surgery. One hospital added fentanyl for analgesic
 Open Access

Table 1  Results of the international survey for type and dose of analgesics in children after cardiac surgery

bmjpo: first published as 10.1136/bmjpo-2017-000046 on 5 July 2017. Downloaded from http://bmjpaedsopen.bmj.com/ on 28 April 2018 by guest. Protected by copyright.
Neonates 0–28 days Infants 29 days–2 years
Use in hospitals Use in hospitals
Medication (n) doses (n) doses
Morphine IV bolus mcg/kg 9 50–200 9 50–500
Morphine IV mcg/kg/h 12 5–40 12 10–60
Piritramide IV bolus mg/kg 1 0.2–1.2 2 0.05–0.4
Piritramide IV mg/kg/day n.a. n.a. 1 1.2
Fentanyl IV bolus mcg/kg 1 1–2 1 1–2
Fentanyl IV mcg/kg/h 3 1–6 3 1–6
Remifentanil IV bolus mcg/kg 1 1 1 1
Remifentanil IV mcg/kg/min 1 0.1–0.2 1 0.1–0.2
Sufentanil IV mcg/kg/h 1 1–2 1 1–2
Dexmedotomidine IV bolus mcg/kg n.a. n.a. 1 50
Dexmedetomidine IV mcg/kg/h n.a. n.a. 2 0.5–1.5
Paracetamol IV mg/kg 5 7.5 7 7.5–15
Paracetamol PO/PR mg/kg/day 5 45–90 7 45–90
Metamizol IV mg/kg 1 40 1 40
Diclofenac IV/PR mg/kg/day n.a. n.a. 3 1–3
Ibuprofen PO bolus mg/kg n.a. n.a. 2 5–10
Dexketoprofen IV mg/kg 1 0.5–1 1 0.5–1
Hospitals represented in the survey: Erasmus MC-Sophia, Rotterdam; LUMC, Leiden; UMC Utrecht; UMC Groningen; Our Lady’s
Children’s Hospital, Crumlin; Children’s Hospital Bambino Gesù, Rome; Royal Brompton Hospital, London; Royal Children’s Hospital,
Melbourne; University Hospital, Leuven; University Hospital La Paz, Madrid; Starship Children’s Hospital, Auckland; Hospital for Sick
Children, Toronto; German Heart Centre, Munich; and Queen Silvia Hospital Gothenburg, Memorial Hospital – Child Health Centre,
Warsaw. PO, per oral; PR, per rectal.

Table 2  Results of the international survey for type and dose of sedatives in children after cardiac surgery
Neonates 0–28 days
Medication Use in hospitals (n) doses
Midazolam IV bolus mg/kg 12 0.05–1.5
Midazolam IV mg/kg/h 15 0.06–4
Clonidine IV bolus mcg/kg 3 0.5–2
Clonidine IV mcg/kg/h 7 0.5–2
Lorazepam PO mg/kg 3 0.05
Propofol IV bolus mg/kg 3 1
Propofol IV mg/kg/h 3 1–6
Esketamine IV bolus mg/kg 1 0.5–1
Esketamine IV mg/kg/h 1 0.5–1.5
Chloral hydrate IV mg/kg 3 10–50
Chloral hydrate NG mg/kg 1 12.5–25
Promethazine mg/kg 1 0.5–1.5
Chlorpromazine mg/kg 2 0.5–1.5
Hospitals represented in the survey: see table 1.
NG, nasogastric; PO, per oral.
Infants 29 days–2 years
Use in hospitals (n) doses
12 0.05–1.5
15 0.06–0.5
3 0.5–2
7 0.5–2
3 0.05
3 1
3 1–6
1 0.5–1
1 0.5–1.5
3 10–50
1 12.5–25
1 0.5–1.5
2 0.5–1.5

Zeilmaker-Roest GA, et al. BMJ Paediatrics Open 2017;1:e000046. doi:10.1136/bmjpo-2017-000046 3

Open Access

therapy in patients returning from the operating room hospitals who routinely use sedatives with pain treatment
with an open sternum. used piritramide (dose 1.2 mg/kg/day) and fentanyl

Analgesics
Opioids were the preferred analgesic; morphine was
the opioid of choice in 13 (87%) of the hospitals.
Dosing ranged from 10 to 60 mcg/kg/h for a contin-
uous infusion and from 50 to 500 mcg/kg for a bolus
dose. Morphine was supplemented with a second anal-
gesic in 73% of hospitals, either as standard practice
or rescue therapy. The primary choice of analgesics
varied between hospitals but did not differ between
age groups within hospitals. Most drugs were dosed
according to weight. However, overall dosing ranges
in neonates tended to be lower compared with infants
and children. Furthermore in children over 2 years of
age more alternative analgesic drugs were reported as
used per protocol in some hospitals, namely oxyco-
done, nalbuphine and diclofenac.
Dexmedetomidine could be considered a sedative but
was reported as an analgesic in the survey and therefore
reported as such.
Sedatives
Midazolam was the primary sedative in 100% of hospitals,
either as a bolus or a continuous infusion. Eight hospi-
tals (53%) reported routine use of sedatives with pain
treatment. The other hospitals only started sedatives in
response to discomfort. Of eight hospitals who routinely
use sedatives with pain treatment, six used morphine as
primary analgesic in an average dose of 10–30 mcg/kg/h
with one outlier using morphine from 30 to 60 mcg/
kg/h, in neonates and infants, respectively. Two other
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(dose 5 mcg/kg/h) as primary analgesics. Average
dosing of morphine in hospitals without routine sedation
was 5–40 mcg/kg/h. Overall morphine dosing in hospi-
tals that use standard sedatives are comparable or lower
than hospitals that do not use standard sedatives.
Sedatives were used as per protocol or at the attending
physician’s discretion. Treatment strategies between
neonates and infants varied less for sedatives than for
analgesics. There were no reported differences in choice
of drugs and dosing between infants 29 days–2 years and
children older than 2 years.
Sedation scores
All hospitals used a validated pain and sedation score.
Table 3 shows the different scores used. Pain and seda-
tion was assessed using a total of six different paediatric
pain and four different sedation scores. Eleven (73%) of
the 15 hospitals used the COMFORT-Behavioural scale
and Numeric Rating Scale (NRS) for pain and seda-
tion. Frequency of pain and sedation assessment varies
between hospitals. Reassessment after an intervention,
either medical or non-medical, was reported by two
respondents.
Each centre reported the use of a local protocol to
guide analgosedation after cardiac surgery.
Discussion
The choice and dosing regimens of analgesics and seda-
tives after cardiac surgery in children varied extensively

Table 3  PD tools reported in the survey

How often assessed
first 72 hours after
surgery?
Scale Validated age range Number of centres Minimal and maximal
Pain assessment
 FLACC (33) 2 months–7 years 2 n.s.
 CRIES (34) 0–28 days 1 n.s.
 COMFORT-B scale (35-37) 0–3 years 1 n.s.
 VAS pain obs 0–3 years 7 8 hourly, after bolus
 NRS pain obs 0–3 years 4 2–4 hourly, after bolus
 LLanto scale 1 n.s.
Sedation assessment
 NISS (38) 0–18 years 2 8 hourly, after bolus
 COMFORT-B scale (38) 0–18 years 11 4–8 hourly, after bolus
 Brussels Sedation Scale (39) Adults 1 n.s.
 Ashworth scale (40) 1 n.s.
COMFORT-B, COMFORT-behavioural scale; CRIES, Crying, Requires O2 for SaO2 <95%, Increased vital signs (blood pressure and
heart rate), Expression, Sleepless; FLACC, Face, Legs, Activity, Cry, Consolability; LLANTO SCALE, llanto, actitud, normorrespiración,
tono postural y observación (crying, attitude, respiratory pattern, muscle tone and facial); NISS, Nurses’ Interpretation of Sedation Score; 
NRS, Numeric Rating Scale pain observation; n.s., not specified; VASobs, Visual Analogue Scale observation.

4 Zeilmaker-Roest GA, et al. BMJ Paediatrics Open 2017;1:e000046. doi:10.1136/bmjpo-2017-000046


across the globe. Opioids were the analgesics of choice.
Morphine was the preferred analgesic drug, with a wide
range of doses, both for continuous infusion and bolus
administration in both the neonatal age group and in
older infants and children. Morphine was supplemented
by a second analgesic drug in 73% of the surveyed hospi-
tals. Differences between local protocols were evident
in all age groups; however, more variation in analge-
sics and sedatives was found in infants and children as
compared with neonates. The underlying cardiac diag-
nosis, severity score or type of surgery did not result in
different treatment algorithms or dosing regimens. Eight
hospitals routinely used a sedative in combination with
pain treatment, all other hospitals started sedatives only
in response to a clinical need for sedation.
The reported use of drugs are comparable with those
described by Wolf in 2011 and reflect in part the guide-
lines from the Royal College of Paediatrics and Child
Health (UK) as well as the guidelines from the Association
of Paediatric Anaesthetists of Great Britain and Ireland.7 8
The recent consensus statement by Lucas et al describes
the pharmacotherapies currently available to manage
pain and sedation in paediatric cardiac critical care
patients and summarises dosing recommendations from
available literature.13 Lucas and colleagues conclude that
a more individualised analgesic and sedative treatment
strategy is necessary to provide optimal care without
adverse effects resulting from pharmacotherapy.
This need for individualised dosing is possibly reflected
in the reported wide range of dosing for morphine with
the highest morphine infusion rate of 60 mcg/kg/h and
largest bolus of 500 mcg/kg in the participating centres
as well as the use of adjuvant analgesics and sedatives.
However, doses mainly differed between hospitals, not
within hospitals. Differences in morphine dosing could
also reflect differences in local practices and preferences
between hospitals rather than individualised dosing regi-
mens based on clear PD endpoints.
Ideally we would like to predict individual morphine
requirement beforehand and better categorise the effi-
cacy of adjuvant or alternative analgesics to minimise
adverse effects. Advances towards precision medicine
have been made for morphine in non-cardiac surgery
patients mainly focusing on the patients’ size, matu-
ration and organ function.6 15 16 By using information
from PK/PD studies on morphine consumption after
cardiac surgery, we aim to individualise and assess treat-
ment effect by regular pain and sedation assessment
and tracking of adverse drug reactions. However, PK
parameters of analgesics and sedatives, or potential PK
alterations in children after cardiac surgery are currently
incomplete. Changes of clearance and volume of distri-
bution would be expected in this cohort, dependent on
the use of the CPB, age and underlying pathology. For
remifentanil,17 18 dexmedetomidine,19 20 clonidine21 and
ketamine,22 studies have been published within the last 10
years with PK parameters in neonates and children after
cardiac surgery. However, these studies show conflicting
Zeilmaker-Roest GA, et al. BMJ Paediatrics Open 2017;1:e000046. doi:10.1136/bmjpo-2017-000046
Open Access
results on PK alterations and most lack PD endpoints
to assess efficacy, making it difficult to implement dose
bmjpo: first published as 10.1136/bmjpo-2017-000046 on 5 July 2017. Downloaded from http://bmjpaedsopen.bmj.com/ on 28 April 2018 by guest. Protected by copyright.
recommendations in clinical practice.
Due to polypharmacy, it is difficult to assess the efficacy
and safety of individual drugs. Our survey showed that a
multimodal drug approach is often used for analgesics
and sedatives. The challenge is to determine how these
drugs interact.23 24 The combination of sedatives and
opioids may contribute to oversedation, which is highly
undesirable and could lead to longer PICU stay, longer
ventilation times, drug tolerance and dependence.25
PD aspects after cardiac surgery are rarely described in
literature, making interpretation of PK knowledge clini-
cally limited. Validated PD scoring tools were used in our
survey hospitals, mainly the COMFORT-B scale (73%),
VAS (47%) and the NRS (26%). Interpretation of some
scores can be problematic, because of poor validation
in neonates and infants after cardiac surgery. Moreover,
items for rises in blood pressure and heart rate are less
useful in children after cardiac surgery because of the use
of inotropic agents.
This study has several limitations. Clinical practice may
deviate from protocol that might not be reflected in the
survey. Also, the participating hospitals are all based in
developed countries, mostly in Europe. Although the
data from our study seem to reflect the day-to-day prac-
tice of analgosedation after cardiac surgery in children,
we cannot rule out that some selection of the hospitals
that were approached and that responded may have an
effect on the diversity of the findings. A larger survey
might increase the amount of variability or show more
consensus within countries.
Conclusion
This survey shows that there is large variability in both
dosing and choice of analgosedative drugs used in
paediatric postcardiothoracic surgery patients espe-
cially between hospitals. This large variability reflects the
complexity of analgosedation in these vulnerable patients
and highlights the need for clinical studies combining PK
with validated PD outcomes. Such studies are necessary
to understand specific changes in this population and
permit evidence-based and personalised treatment proto-
cols.
Acknowledgements  The authors like to acknowledge all contributors to the
survey. The authors would like to thank Professor Dr Karel Allegaert and Professor
Dr John van der Anker for their editorial comments.
Competing interests  None declared.
Provenance and peer review  Not commissioned; externally peer reviewed.
Open Access  This is an Open Access article distributed in accordance with the
Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which
permits others to distribute, remix, adapt, build upon this work non-commercially,
and license their derivative works on different terms, provided the original work is
properly cited and the use is non-commercial. See: http://​creativecommons.​org/​
licenses/​by-​nc/​4.​0/
© Article author(s) (or their employer(s) unless otherwise stated in the text of the
article) 2017. All rights reserved. No commercial use is permitted unless otherwise
expressly granted.
5
 Open Access
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